amitriptyline hydrochloride
Elavil, Levate ◆, Novotriptyn ◆

Available forms
Available by prescription only
Injection: 10 mg/ml
Tablets: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg

Indications and dosages
 Depression, anorexia or bulimia related to depression ◇, adjunctive treatment of neurogenic pain ◇. Adults: Initial outpatient, 75 to 100 mg P.O. daily in divided doses or 50 to 150 mg h.s. Inpatient, 100 to 300 mg daily. I.M. dosage is 20 to 30 mg q.i.d., which should be changed to oral route as soon as possible. Maintenance dosage is 50 to 100 mg daily.
≡ Dosage adjustment. For geriatric or adolescent patients, 10 mg P.O. t.i.d. and 20 mg h.s.

Pharmacodynamics
Antidepressant action: Amitriptyline is thought to exert its antidepressant effects by inhibiting reuptake of norepinephrine and serotonin in CNS nerve terminals (presynaptic neurons), resulting in increased concentrations and enhanced activity of these neurotransmitters in the synaptic cleft. Amitriptyline more actively inhibits reuptake of serotonin than norepinephrine; it carries a high risk of undesirable sedation, but tolerance to this effect usually develops within a few weeks.

Pharmacokinetics
Absorption: Absorbed rapidly from the GI tract after oral administration and from muscle tissue after I.M. administration.
Distribution: Distributed widely into the body, including the CNS and breast milk; 96% protein-bound.
Metabolism: Metabolized by the liver to the active metabolite nortriptyline; a significant first-pass effect may account for variability of serum concentrations in different patients taking the same dosage.
Excretion: Excreted mostly in urine.

Contraindications and precautions
Contraindicated in patients in acute recovery phase of MI, in patients hypersensitive to drug, and in patients who have taken an MAO inhibitor within the past 14 days.
  Use cautiously in patients with recent history of MI and in those with unstable heart disease or renal or hepatic impairment.

Interactions
Drug-drug. Antiarrhythmics (disopyramide, procainamide, quinidine), pimozide, thyroid hormones: May increase risk of arrhythmias and conduction defects. Avoid use together.
Anticholinergics (including antihistamines, antiparkinsonians, atropine, meperidine, phenothiazines): May cause oversedation, paralytic ileus, visual changes, and severe constipation. Monitor clinical effects closely.
Barbiturates: Induce metabolism and decrease therapeutic efficacy of amitriptyline. Monitor drug effects closely.
Beta blockers, cimetidine, hormonal contraceptives, methylphenidate, propoxyphene, selective serotonin reuptake inhibitors: May inhibit amitriptyline metabolism, increasing plasma levels and toxicity. Use together cautiously.
Centrally acting antihypertensives (such as clonidine, guanabenz, guanadrel, guanethidine, methyldopa, reserpine): May decrease hypotensive effects of these drugs. Monitor blood pressure.
CNS depressants (including analgesics, anesthetics, barbiturates, narcotics, tranquilizers): Increases sedation. Monitor drug effects closely.
Disulfiram, ethchlorvynol: May cause delirium and tachycardia. Avoid use together.
Haloperidol, phenothiazines: Decrease amitriptyline metabolism and efficacy. Avoid use together.
Metrizamide: Increases risk of seizures. Avoid use together.
Sympathomimetics, including epinephrine, phenylephrine, and ephedrine (commonly found in nasal sprays): May increase blood pressure. Monitor patient’s blood pressure.
Warfarin: May increase PT and cause bleeding. Monitor PT and INR, and decrease warfarin dosage.
Drug-herb. Evening primrose oil: May cause additive or synergistic effect, resulting in lower seizure threshold and increased risk of seizures. Discourage use together.
Drug-lifestyle. Alcohol use: Additive effects are likely. Discourage alcohol use.
Heavy smoking: Induces amitriptyline metabolism and decreases therapeutic efficacy. Discourage smoking.
Sun exposure: May cause photosensitivity reactions. Advise patient to take precautions.

Adverse reactions
CNS: coma, seizures, hallucinations, delusions, disorientation, ataxia, tremor, peripheral neuropathy, anxiety, insomnia, restlessness, drowsiness, dizziness, weakness, fatigue, headache, extrapyramidal reactions.
CV: edema, MI, CVA, arrhythmias, heart block, orthostatic hypotension, tachycardia, ECG changes, hypertension.
EENT: blurred vision, tinnitus, mydriasis, increased intraocular pressure.
GI: dry mouth, nausea, vomiting, anorexia, epigastric distress, diarrhea, constipation, paralytic ileus.
GU: urine retention.
Hematologic: agranulocytosis, thrombocytopenia, leukopenia, eosinophilia.
Hepatic: liver dysfunction.
Metabolic: hyperglycemia, hypoglycemia.
Skin: diaphoresis, rash, urticaria, photosensitivity.
Other: hypersensitivity reaction.

Effects on lab test results
• May increase or decrease glucose levels.
• May increase eosinophil count and liver function test values. May decrease granulocyte, platelet, and WBC counts.

Overdose and treatment
The first 12 hours after acute ingestion are a stimulatory phase characterized by excessive anticholinergic activity (agitation, irritation, confusion, hallucinations, hyperthermia, parkinsonian symptoms, seizure, urine retention, dry mucous membranes, pupillary dilation, constipation, and ileus). This is followed by CNS depressant effects, including hypothermia, decreased or absent reflexes, sedation, hypotension, cyanosis, and cardiac irregularities, including tachycardia, conduction disturbances, and quinidine-like effects on the ECG.
 Severity of overdose is best indicated by widening of the QRS complex and usually represents a serum level in excess of 1,000 mg/ml; metabolic acidosis may follow hypotension, hypoventilation, and seizures. Delayed cardiac anomalies and death may occur.
 Treatment is symptomatic and supportive, including maintaining airway, stable body temperature, and fluid and electrolyte balance. Induce emesis with ipecac if gag reflex is intact; follow with gastric lavage and activated charcoal to prevent further absorption. Dialysis is of little use. Physostigmine may be cautiously used to reverse the symptoms of tricyclic antidepressant poisoning in life-threatening situations. Treatment of seizures may include parenteral diazepam or phenytoin; treatment of arrhythmias, parenteral phenytoin or lidocaine; and treatment of acidosis, sodium bicarbonate. Don’t give barbiturates; these may enhance CNS and respiratory depressant effects.

Special considerations
• Drug may be used to prevent migraine and cluster headaches, intractable hiccups, and posttherapeutic neuralgia.
• Amitriptyline causes a high risk of sedative effects. Tolerance to sedative effects may develop over several weeks.
• The full dose may be given at bedtime to help offset daytime sedation.
• Substitute oral administration route for parenteral route as soon as possible.
 ALERT Parenteral form of drug is for I.M. administration only. Drug shouldn’t be given I.V.
• I.M. administration may result in a more rapid onset of action than oral administration.
• Discontinue drug at least 48 hours before surgical procedures.
• Sugarless chewing gum, hard candy, or ice may alleviate dry mouth. Stress the importance of regular dental hygiene because dry mouth can increase the risk of dental caries.
• Depressed patients, particularly those with known manic depressive illness, may experience a shift to mania or hypomania.
• Check vital signs regularly for decreased blood pressure or tachycardia; observe patient carefully for adverse reactions and report changes. Obtain ECG in patients older than age 40 before starting therapy. Advise patient to take the first dose in the office to allow close observation for adverse reactions.
• Check for anticholinergic adverse reactions, which may require dosage reduction.
• Observe patient for mood changes to monitor progress; benefits may not occur for several (3 to 6) weeks.
• Don’t withdraw drug abruptly. After abrupt withdrawal of long-term therapy, patient may experience nausea, headache, or malaise. This doesn’t indicate addiction. When discontinuing, reduce dose slowly.
Breast-feeding patients
• Drug appears in breast milk at levels equal to or greater than those in maternal serum. About 1% of ingested dose appears in the breast-fed infant’s serum. The potential benefit to the woman should outweigh the possible adverse reactions in the infant.
Pediatric patients
• Drug isn’t recommended for children younger than age 12.
Geriatric patients
• Geriatric patients may be at greater risk for adverse cardiac effects.

Patient education
• Tell patient to take drug exactly as prescribed and not to double missed doses.
• Advise patient that full dose may be taken at bedtime to alleviate daytime sedation. Alternatively, it may be taken in the early evening to avoid morning hangover.
• Explain that full effects of drug may not become apparent for up to 4 weeks.
• Warn patient that drug may cause drowsiness or dizziness. Tell him to avoid hazardous activities that require alertness until full effects of drug are known.
• Warn patient not to drink alcoholic beverages while taking drug.
• Suggest taking drug with food or milk if it causes stomach upset and using sugarless gum or candy to relieve dry mouth.
• After initial doses, advise patient to lie down for about 30 minutes and to rise slowly to prevent dizziness or fainting.
• Warn patient not to stop taking drug suddenly.
• Encourage patient to report troublesome or unusual effects, especially confusion, movement disorders, rapid heartbeat, dizziness, fainting, or difficulty urinating.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use